N714K
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialAsparagine → Lysine at position 714 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications. AlphaMissense 0.992 (near-maximum), DynaMut2 ΔΔG -0.44 kcal/mol (destabilising). The FOURTH Atlas variant at position 714 (with N714T, N714S, and D771H in the same network).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | I712 | Gained |
| Hydrogen bond | A716 | — | Lost |
| Hydrogen bond | E717 | E717 | Preserved |
| Hydrogen bond | S718 | S718 | Preserved |
| Hydrogen bond | I767 | — | Lost |
| Hydrogen bond | D771 | — | Lost |
| Polar contact | — | I712 | Gained |
| Polar contact | A716 | — | Lost |
| Polar contact | E717 | E717 | Preserved |
| Polar contact | S718 | S718 | Preserved |
| Polar contact | I767 | — | Lost |
| Polar contact | D771 | D771 | Preserved |
| Van der Waals | — | I712 | Gained |
| Van der Waals | A716 | — | Lost |
| Van der Waals | E717 | — | Lost |
| Van der Waals | — | S718 | Gained |
| Hydrophobic | — | I712 | Gained |
| Hydrophobic | E717 | E717 | Preserved |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
Structural Context
Position 714 same neighbor environment as N714T/N714S: SER715 (2.4 Å), ASP713 (2.5 Å), PHE770 (4.4 Å), ALA716 (4.4 Å), ASP771 (4.7 Å).
Replacing N714 with lysine introduces a positive charge into the D713-D771 polar network — adjacent to two existing negative charges. The K714 amine likely forms salt bridges with D713 and/or D771, restructuring the polar network entirely (where the wild-type N714 amide H-bonded but did not carry charge).
The |ΔΔG| of 0.44 reflects fold accommodation. AlphaMissense's 0.992 (near-maximum) confirms severe functional consequence — the charge introduction disrupts the wild-type partner-recognition geometry.
Druggability Assessment
Mechanism is charge introduction into the D713-D771 polar network. Therapeutic strategy: same microregion as N714T, N714S, D771H.
Why this matters
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